Complex causal association between genetically predicted 731 immunocyte phenotype and osteonecrosis: A bidirectional Two-sample mendelian randomization analysis.

PURPOSE: Previous studies have explored the role of immune cells on osteonecrosis. This Mendelian randomization (MR) study further assessed 731 immunocyte phenotypes on osteonecrosis whether a causal relationship exists and provides some evidence of causality. METHODS: The 731 immunocyte phenotypes and osteonecrosis data used in this study were obtained from their respective genome-wide association studies (GWAS). We used inverse variable weighting (IVW) as the primary analysis method. In addition, we simultaneously employed multiple analytical methods, including MR-Egger, weighted mode, simple mode, and weighted median, to strengthen the final results. Finally, sensitivity analyses were conducted to verify the stability and feasibility of the data. RESULTS: The results of the IVW method of MR analysis showed that 8 immunocyte phenotypes were positively associated with osteonecrosis (P<0.05, OR > 1); 18 immunocyte phenotypes were negatively associated with osteonecrosis (P<0.05, OR<1), none of which were heterogeneous or horizontally pleiotropic (P > 0.05) or reverse causality. In addition to this, in reverse MR, osteonecrosis was positively associated with 10 additional immunocyte phenotypes (P<0.05, OR > 1) and negatively associated with 14 immunocyte phenotypes (P<0.05, OR<1). And none of them had heterogeneity and horizontal pleiotropy (P > 0.05) or reverse causality. CONCLUSIONS: We demonstrated a complex causal relationship between multiple immune phenotypes and osteonecrosis through a comprehensive two-way two-sample MR analysis, highlighting the complex pattern of interactions between the immune system and osteonecrosis.

No evidence of genetic causality between diabetes and osteonecrosis: a bidirectional two-sample Mendelian randomization analysis.

OBJECTIVE: This study aimed to examine whether diabetes mellitus is causally associated with osteonecrosis. METHOD: Using publicly accessible genome-wide association study statistics, a bidirectional two-sample Mendelian randomization analysis was carried out. In order to determine whether diabetes has a causal effect on osteonecrosis and whether osteonecrosis has a causal effect on diabetes, we extracted six date on diabetes in Europeans from IEU OpenGWAS and GWAS Catalogue and osteonecrosis in Europeans from FinnGen. We then evaluated the data using inverse variance weighting, MR-Egger regression, weighted median, weighted mode, and simple mode. The results' stability and dependability were then evaluated using sensitivity analysis and heterogeneity analysis. Finally, meta-analysis is used to further confirm if there is a relationship between diabetes and osteonecrosis. RESULTS: When diabetes was used as an exposure factor, MR-Egger regression showed that directional fold product was unlikely to bias the results. Cochran's Q test showed only minor heterogeneity in a few data sets. Multidirectional tests Egger-intercept, MR-PRESSO and funnel plots for most data did not show multidirectional and asymmetry at the gene level. Most of the IVW results showed no causal relationship between diabetes mellitus and osteonecrosis. The results of meta-analysis of IVW methods further confirmed the absence of a causal relationship. Inverse MR analysis also showed no causal relationship between osteonecrosis and diabetes. CONCLUSION: Results of bidirectional MR analysis show no evidence of causal relationship between diabetes and osteonecrosis.

Prostaglandin E1 attenuates high glucose-induced apoptosis in proximal renal tubular cells by inhibiting the JNK/Bim pathway.

Proximal renal tubular damage is a critical process underlying diabetic kidney disease (DKD). Our previous study shows that prostaglandin E1 (PGE1) reduces the apoptosis of renal tubular cells in DKD rats. But its underlying mechanisms remain unclear. In this study we investigated the protective effects of PGE1 in DKD rats and high glucose (HG, 30 mM)-treated HK-2 proximal tubular cells. Four weeks after uninephrectomized streptozotocin-induced diabetic rats were established, the DKD rats were administered PGE1 (10 µg· kg-1· d-1, iv.) for 10 consecutive days. We showed that PGE1 administration did not change blood glucose levels, but alleviated diabetic kidney injury in the DKD rats, evidenced by markedly reduced proteinuria and renal tubular apoptosis. In the in vitro experiments, PGE1 (0.1-100 µM) significantly enhanced HG-reduced HK-2 cell viability. In HG-treated HK-2 cells, PGE1 (10 µM) significantly suppressed the c-Jun N-terminal kinase (JNK) and the mitochondrial apoptosis-related protein expressions such as Bim, Bax, caspase-3 and cleaved caspase-3; similar changes were also observed in the kidney of PGE1-treated DKD rats. By using two pharmacological tools-JNK activator anisomycin (AM) and JNK inhibitor SP600125, we revealed that PGE1 blocked HG-triggered activation of JNK/Bim pathway in HK-2 cells; JNK was an upstream regulator of Bim. In conclusion, our results demonstrate that the nephroprotective effects of PGE1 against apoptosis of proximal renal tubule in DKD rats via suppressing JNK-related Bim signaling pathway.

Silencing of LncRNA BDNF-AS attenuates Aß25-35-induced neurotoxicity in PC12 cells by suppressing cell apoptosis and oxidative stress.

OBJECTIVE: To explore the effects of long non-coding RNA (lncRNA) brain-derived neurotrophic factor anti-sense (BDNF-AS) on the Aß25-35-induced neurotoxicity in PC12 cells. METHODS: PC12 cells were induced by Aß25-35 to construct cell injury models of Alzheimer's disease (AD), and then transfected with siRNA-BDNF-AS. Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to detect the expressions of BDNF-AS and BDNF. Besides, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Hoechst33342 staining were utilized to analyze the cell viability and apoptosis, respectively, Western blotting to evaluate the protein expressions, immunofluorescence to assess the Cytochrome C (Cyt C) release, and Rhodamine 123 (Rh123) to measure the mitochondrial membrane potential (MMP).The evaluation of oxidative stress was conducted via the determination of the levels of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT). RESULTS: Aß25-35 apparently increased BDNF-AS but decreased BDNF in PC12 cells, which also reduced viability and induced apoptosis of PC12 cells. Silencing of BDNF-AS could significantly up-regulate BDNF in Aß25-35-induced PC12 cells, with the elevated cell viability. Moreover, silencing BDNF-AS inhibited the apoptosis of Aß25-35-induced PC12 cells, suppressed the release of Cyt C, reduced the expression of cleaved caspase-3 and Bax, and lowered the mean fluorescence intensity (MFI) of Rh123, but it elevated the expression of Bcl-2. Besides, silencing BDNF-AS also reduced ROS intensity and MDA content, but enhanced the activities of SOD and CAT. CONCLUSION: Silencing BDNF-AS exerts protective functions to increase the viability, inhibit the apoptosis and oxidative stress of Aß25-35-induced PC12 cells by negative regulation of BDNF. ABBREVIATIONS: Aß25-35: amyloid beta peptide 25-35; AD: Alzheimer's disease; LncRNA BDNF-AS: long non-coding RNA brain-derived neurotrophic factor anti-sense; OS: Oxidative stress.

Prognostic Value of microRNA-224 in Various Cancers: A Meta-analysis.

BACKGROUND: During previous studies, microRNA-224 (miR-224) was frequently investigated and discovered to be of vital significance to prognosis of patients with various cancers. However, its accurate prognostic value has not been estimated worldwide. Herein, we performed meta-analysis to assess its potential predictive value in a variety of human tumors. METHODS: Qualified researches were identified up to March 1, 2017 through performing online searches in PubMed, EMBASE, Web of Science and Cochrane Database of Systematic Reviews. Overall survival (OS), disease-free survival (DFS) or progression-free survival (PFS) as a prognosis for various cancers were extracted and calculated, if available. Pooled hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Stata version 13.0 (StataCorp, College Station, Texas, USA). RESULTS: 22 eligible studies with 3000 patients were ultimately brought into the current meta-analysis. It suggested that high miR-224 expression was significantly associated with poor OS in tissue (HR = 1.43, 95% CI = 1.00-2.03). During multivariate analysis, high miR-224 expression was more significantly associated with OS in tissue (HR = 2.81, 95% CI = 1.91-4.13). Likewise, there were significant associations between tissue miR-224 expression and colorectal cancer (CRC), diffuse large B-cell lymphoma (DLBCL) and gastric cancer (GC) patients (p <0.05). Nevertheless, there were not significant associations between high tissue miR-224 expression and DFS (HR = 2.15, 95% CI = 0.97-4.79) or PFS (HR = 0.92, 95% CI = 0.53-1.59). CONCLUSION: As far as the present researches are concerned, tissue miR-224 has a significantly prognostic value in various cancers, especially in CRC, DLBCL and GC. Due to the complicated pathogenesis of cancers, more large-scale and standard researches are requisite.

Association of LPP and TAGAP Polymorphisms with Celiac Disease Risk: A Meta-Analysis.

Background: Lipoma preferred partner (LPP) and T-cell activation Rho GTPase activating protein (TAGAP) polymorphisms might influence the susceptibility to celiac disease. Therefore, we performed a meta-analysis by identifying relevant studies to estimate the risks of these polymorphisms on celiac disease. Methods: The PubMed, Web of Science and Embase databases were searched (up to October 2016) for LPP rs1464510 and TAGAP rs1738074 polymorphisms. Results: This meta-analysis included the same 7 studies for LPP rs1464510 and TAGAP rs1738074. The minor risk A allele at both rs1464510 and rs1738074 carried risks (odds ratios) of 1.26 (95% CI: 1.22-1.30) and 1.17 (95% CI: 1.14-1.21), respectively, which contributed to increased risks in all celiac disease patients by 10.72% and 6.59%, respectively. The estimated lambdas were 0.512 and 0.496, respectively, suggesting that a co-dominant model would be suitable for both gene effects. Conclusions: This meta-analysis provides robust estimates that polymorphisms in LPP and TAGAP genes are potential risk factors for celiac disease in European and American. Prospective studies and more genome-wide association studies (GWAS) are needed to confirm these findings, and some corresponding molecular biology experiments should be carried out to clarify the pathogenic mechanisms of celiac disease.

Prognostic value of microRNAs in hepatocellular carcinoma: a meta-analysis.

BACKGROUND: Numerous articles reported that dysregulated expression levels of miRNAs correlated with survival time of HCC patients. However, there has not been a comprehensive meta-analysis to evaluate the accurate prognostic value of miRNAs in HCC. DESIGN: Meta-analysis. MATERIALS AND METHODS: Studies, published in English, estimating expression levels of miRNAs with any survival curves in HCC were identified up until 15 April, 2017 by performing online searches in PubMed, EMBASE, Web of Science and Cochrane Database of Systematic Reviews by two independent authors. The pooled hazard ratios (HR) with 95% confidence intervals (CI) were used to estimate the correlation between miRNA expression and overall survival (OS). RESULTS: 54 relevant articles about 16 miRNAs, with 6464 patients, were ultimately included. HCC patients with high expression of tissue miR-9 (HR = 2.35, 95% CI = 1.46-3.76), miR-21 (HR = 1.76, 95% CI = 1.29-2.41), miR-34c (HR = 1.64, 95% CI = 1.05-2.57), miR-155 (HR = 2.84, 95% CI = 1.46-5.51), miR-221 (HR = 1.76, 95% CI = 1.02-3.04) or low expression of tissue miR-22 (HR = 2.29, 95% CI = 1.63-3.21), miR-29c (HR = 1.35, 95% CI = 1.10-1.65), miR-34a (HR = 1.84, 95% CI = 1.30-2.59), miR-199a (HR = 2.78, 95% CI = 1.89-4.08), miR-200a (HR = 2.64, 95% CI = 1.86-3.77), miR-203 (HR = 2.20, 95% CI = 1.61-3.00) have significantly poor OS (P < 0.05). Likewise, HCC patients with high expression of blood miR-21 (HR = 1.73, 95% CI = 1.07-2.80), miR-192 (HR = 2.42, 95% CI = 1.15-5.10), miR-224 (HR = 1.56, 95% CI = 1.14-2.12) or low expression of blood miR-148a (HR = 2.26, 95% CI = 1.11-4.59) have significantly short OS (P < 0.05). CONCLUSIONS: In conclusion, tissue miR-9, miR-21, miR-22, miR-29c, miR-34a, miR-34c, miR-155, miR-199a, miR-200a, miR-203, miR-221 and blood miR-21, miR-148a, miR-192, miR-224 demonstrate significantly prognostic value. Among them, tissue miR-9, miR-22, miR-155, miR-199a, miR-200a, miR-203 and blood miR-148a, miR-192 are potential prognostic candidates for predicting OS in HCC.

The relationships between HLA class II alleles and antigens with gestational diabetes mellitus: A meta-analysis.

Gestational diabetes mellitus (GDM) is defined as glucose intolerance with onset or first recognition during pregnancy. It is associated with an increased risk of pregnancy complications. Susceptibility to GDM is partly determined by genetics and linked with type 1 diabetes-associated high risk HLA class II genes. However, the evidence for this relationship is still highly controversial. In this study, we assessed the relationship between HLA class II variants and GDM. We performed meta-analysis on all of literatures available in PubMed, Embase, Web of Science and China National Knowledge Infrastructure databases. The odds ratio and 95% confidence interval of each variant were estimated. All statistical analyses were conducted using the Comprehensive Meta Analysis 2.2.064 software. At the allelic analysis, DQB1*02, DQB1*0203, DQB1*0402, DQB1*0602, DRB1*03, DRB1*0301 and DRB1*1302 reached a nominal level of significance, and only DQB1*02, DQB1*0602 and DRB1*1302 were statistically significant after Bonferroni correction. At the serological analysis, none of DQ2, DQ6, DR13 and DR17 was statistically significant following Bonferroni correction although they reached a nominal level of significance. In sum, our meta-analysis demonstrated that there were the associations between HLA class II variants and GDM but more studies are required to elucidate how these variants contribute to GDM susceptibility.

Meta-Analysis on Associations of RGS1 and IL12A Polymorphisms with Celiac Disease Risk.

The pathogenesis of celiac disease (CD) has been related to polymorphisms in the regulator of G-protein signaling 1 (RGS1) and interleukin-12 A (IL12A) genes, but the existing findings are inconsistent. Our aim is to investigate the associations of two single-nucleotide polymorphisms (SNPs) (rs2816316 in RGS1 and rs17810546 in IL12A) with CD risk using meta-analysis. We searched PubMed and Web of Science on RGS1 rs2816316 and IL12A rs17810546 with CD risk. Odds ratio (OR) and 95% confidence interval (CI) of each SNP were estimated. All statistical analyses were performed on Stata 12.0. A total of seven studies were retrieved and analyzed. The available data indicated the minor allele C of rs2816316 was negatively associated with CD (C vs. A: OR = 0.77, 95% CI = 0.74-0.80), and a positive association was found for the minor allele G of rs17810546 (G vs. A: OR = 1.37, 95% CI = 1.31-1.43). The co-dominant model of genotype effect confirmed the significant associations between RGS1 rs2816316/IL12A rs17810546 and CD. No evidence of publication bias was observed. Our meta-analysis supports the associations of RGS1 and IL12A with CD and strongly calls for further studies to better understand the roles of RGS1 and IL12A in the pathogenesis of CD.

Graphene-cyclodextrin-cytochrome c layered assembly with improved electron transfer rate and high supramolecular recognition capability.

This study aimed to develop a new graphene-based layered assembly, named graphene-cyclodextrin-cytochrome c with improved electron transfer rate. This assembly has combined high conductivity of graphene nanosheets (GNs), selectively binding properties and electronegativity of cyclodextrins (CDs), as well as electropositivity of cytochrome c (Cyt c). This assembly can also mimic the confined environments of the intermembrane space of mitochondria. A ß-cyclodextrin (ß-CD) functionalized GN (GN-CD) assembly was initially prepared by a simple wet-chemical strategy, i.e., in situ thermal reduction of graphene oxide with hydrazine hydrate in the presence of ß-CD. Cyt c was then intercalated to the GN-CD assembly to form a layered self-assembled structure, GN-CD-Cyt c, through electrostatic interaction. Compared with GNs and GN-CD, GN-CD-Cyt c assembly displayed improved electron transfer rate and high supramolecular recognition capability toward six probe molecules.

[Investigation on facial profile preferences of orthodontic patients].

PURPOSE: To investigate facial profile preferences of orthodontic patients and determine whether the patient's age and sex were influential factors in the esthetic perception for providing reference for clinical practice. METHODS: Profile digital photographs of each patient were used. Changes in facial convexity were established by altering the position of mandible incrementally with Photoshop 7.0. Thus profile images of various degrees of mandiblular anteroposterior discrepancy for each patient was generated. Then an electronic questionnaire was designed and administered to investigate tolerable boundary values for mandibular retrognathism, tolerable boundary values for mandibular prognathism and most pleasing profiles of 203 subjects (average age 19.2±6.0 years; 70 males, 133 females). Differences between male and female profiles in the esthetic perception of patients were analyzed by Wilcoxon matched-pairs signed ranks test. Comparison of esthetics perception for male and female profiles regarding patient's sex and age was made by Wilcoxon rank sum test of two independent samples. All statistical analysis was performed using SPSS 17.0 software package. RESULTS: The zone of acceptability of facial convexity was 168°-180° for male model and 160°-172° for female model. The most pleasing profile was 172° for male and 168° for female. There was no significant difference between male and female patients in facial profile preferences (P>0.05). The differences in facial profile preferences between adult group and immature group were statistically significant (P<0.05). In the comparison of age groups, the adult group preferred bigger facial convexity angles than immature group for male and female retrognathia profile, male prognathia profile and male most pleasing profile. CONCLUSIONS: The zone of acceptability of facial convexity and the most pleasing profile exist in patients' esthetic perception of profile. There is difference between male and female profiles in the esthetic perception. The facial profile preferences of orthodontic patients are influenced by age, not by sex.